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11.
Wertz IE Kusam S Lam C Okamoto T Sandoval W Anderson DJ Helgason E Ernst JA Eby M Liu J Belmont LD Kaminker JS O'Rourke KM Pujara K Kohli PB Johnson AR Chiu ML Lill JR Jackson PK Fairbrother WJ Seshagiri S Ludlam MJ Leong KG Dueber EC Maecker H Huang DC Dixit VM 《Nature》2011,471(7336):110-114
Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics. 相似文献
12.
Helicases are vital enzymes that carry out strand separation of duplex nucleic acids during replication, repair and recombination. Bacteriophage T7 gene product 4 is a model hexameric helicase that has been observed to use dTTP, but not ATP, to unwind double-stranded (ds)DNA as it translocates from 5' to 3' along single-stranded (ss)DNA. Whether and how different subunits of the helicase coordinate their chemo-mechanical activities and DNA binding during translocation is still under debate. Here we address this question using a single-molecule approach to monitor helicase unwinding. We found that T7 helicase does in fact unwind dsDNA in the presence of ATP and that the unwinding rate is even faster than that with dTTP. However, unwinding traces showed a remarkable sawtooth pattern where processive unwinding was repeatedly interrupted by sudden slippage events, ultimately preventing unwinding over a substantial distance. This behaviour was not observed with dTTP alone and was greatly reduced when ATP solution was supplemented with a small amount of dTTP. These findings presented an opportunity to use nucleotide mixtures to investigate helicase subunit coordination. We found that T7 helicase binds and hydrolyses ATP and dTTP by competitive kinetics such that the unwinding rate is dictated simply by their respective maximum rates V(max), Michaelis constants K(M) and concentrations. In contrast, processivity does not follow a simple competitive behaviour and shows a cooperative dependence on nucleotide concentrations. This does not agree with an uncoordinated mechanism where each subunit functions independently, but supports a model where nearly all subunits coordinate their chemo-mechanical activities and DNA binding. Our data indicate that only one subunit at a time can accept a nucleotide while other subunits are nucleotide-ligated and thus they interact with the DNA to ensure processivity. Such subunit coordination may be general to many ring-shaped helicases and reveals a potential mechanism for regulation of DNA unwinding during replication. 相似文献
13.
Spatio-temporal transcriptome of the human brain 总被引:1,自引:0,他引:1
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RK Koenekoop H Wang J Majewski X Wang I Lopez H Ren Y Chen Y Li GA Fishman M Genead J Schwartzentruber N Solanki EI Traboulsi J Cheng CV Logan M McKibbin BE Hayward DA Parry CA Johnson M Nageeb;Finding of Rare Disease Genes 《Nature genetics》2012,44(9):1035-1039
Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wld(s)) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder. 相似文献
16.
We describe a case study evaluating the ecological impact of Bromus tectorum L. (cheatgrass) invasion following fire disturbance and the effectiveness of revegetation as a means of rehabilitation in a degraded semiarid shrubsteppe system. The effectiveness of rehabilitation efforts was assessed relative to arthropod richness, vegetation and arthropod community composition, and ground-cover characteristics in 3 habitats: undisturbed, burned and weed infested ( B. tectorum ), and burned then rehabilitated with native and nonnative vegetation. Arthropods were collected in each habitat using pitfall traps. Differences in arthropod richness were compared using rarefaction curves. Nonmetric multidimensional scaling and nonparametric multivariate statistical procedures, including analysis of similarity and similarity percentage routines, were used to compare arthropod and vegetation community composition and ground-cover characteristics between habitats. Arthropod communities in the rehabilitated habitat were distinct from those observed in the undisturbed and weed-infested habitats. Rehabilitation in this study resulted in a shift toward conditions observed in an undisturbed habitat and perhaps is an intermediate step to complete restoration. Arthropod richness, arthropod and vegetation community composition, and ground-cover characteristics were all useful indicators but returned slightly different results. Assessing multiple variables yielded the most complete understanding of the habitats studied. 相似文献
17.
Reported are 105 species of Scolytidae (Coleoptera) from Idaho. About one-third of these are rarely collected, of which 22 species are known from a single locality each. Twelve species reported from Idaho for the first time are: Carphoborus carri Swaine, C. sansoni Swaine, Phloeosinus hoferi Blackman, Conophthorus monophyllae Hopkins, Dryocoetes betulae Hopkins, Ips confuses (LeConte), Pityophthorus absonus Blackman, P. aquilus Blackman , P. blandus Blackman, P. deletus LeConte, P. sculptor Blackman, and Xyleborinus saxeseni (Ratzeburg). Significant extensions of the known distributions in Idaho are reported for seven other scolytids; Alniphagus aspericollis (LeConte), Dendroctonus murrayanae Hopkins, Phloeotribus lecontei Schedl, Procryphalus mucronatus (LeConte), Trypophloeus populi Hopkins, Xyleborus dispar (Fabricius), and X. intrusus Blandford. Xyleborus dispar especially needs study in anticipation that it may become increasingly important in Idaho fruit trees and other woody plants including ornamentals and shade trees. 相似文献
18.
James E. Johnson 《西北部美国博物学家》2011,46(4)
Crayfish distribution and composition in Utah are poorly documented. Based upon limited collections, the native Pacifastacus gambelii is widespread and often abundant in the Bear and Weber river drainages and is occasionally represented in smaller tributaries to the Great Salt Lake and to the Raft River. Pacifastacus leniusculus was collected from Utah County and Procambarus clarkii from Tooele County; the origin of these populations is not known. The nonnative crayfish Orconectes virilis is currently abundant in the Virgin, Price, and Duchesne river basins and the Glen Canyon, Flaming Gorge, Deer Creek, and Starvation reservoirs; it is expanding in Huntington North, Scofield, and Willard reservoirs. Further work is required to develop a more complete inventory and monitor the impacts on aquatic ecosystems of expanding nonnative crayfish populations. Surreptitious stockings can be dealt with only if the public is made aware of the adverse consequences of ill-conceived introductions. 相似文献
19.
Timothy D. Hatten Norm Merz James B. Ding Johnson Chris Looney Travis Ulrich Scott Soults Roland Capilo Dwight Bergerone Paul Anders Philip Tanimoto Bahman Shafii 《西北部美国博物学家》2011,70(4)
The parasitic wasp Mymaromella pala Huber and Gibson (Hymenoptera: Mymarommatidae) was collected at 4 sites within a canyon reach of the Kootenai River in Lincoln County, Montana. This minute species has only recently been described, but it appears to have a large distribution throughout the United States and to be associated with upland and riparian forests. La avispa parasitaria Mymaromella pala Huber y Gibson (Hymenoptera: Mymarommatidae) se recolectó en cuatro sitios a lo largo de un cañón del Río Kootenai en Lincoln Co., MT. Hace poco que se describió esta especie diminuta, pero parece tener una distribución extensa en los EE.UU. y estar asociada con bosques altos y ribereños. 相似文献
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